Mechanical and thermal stability of adhesive membranes with nonzero bending rigidity.

Membranes at a microscopic scale are affected by thermal fluctuations and self-adhesion due to van der Waals forces. Methods to prepare membranes of even molecular scale, e.g., graphene, have recently been developed, and the question of their mechanical and thermal stability is of crucial importance. To this end we modeled microscopic membranes with an attractive interaction and applied Langevin dynamics. Their behavior was also analyzed under external loading. Even though these membranes folded during isotropic compression as a result of energy minimization, the process at high confinement was similar to crumpling of macroscopic nonadhesive sheets. The main difference appeared when the compression was released. In such cases, for membranes of sufficiently large size, folded or scrolled conformations emerged. At high temperature entropic effects made such conformations unfavorable, however.

Solution for the fragment-size distribution in a crack-branching model of fragmentation.

It is well established that rapidly propagating cracks in brittle material are unstable such that they generate side branches. It is also known that cracks are attracted by free surfaces, which means that they attract each other. This information is used here to formulate a generic model of fragmentation in which the small-size part of the fragment-size distribution results from merged crack branches in the damage zones along the paths of the propagating cracks. This model is solved under rather general assumptions for the fragment-size distribution. The model leads to a generic distribution S(-gamma) exp(-S/S(0)) for fragment sizes S, where gamma = 2d-1/d with d the Euclidean dimension, and S(0) is a material dependent parameter.

A pitfall of metaiodobenzylguanidine scan: paraganglioma in close proximity to adrenocortical adenoma.

We report a potential pitfall of 123I-metaiodobenzylguanine (MIBG) scan. Magnetic resonance imaging performed for other reasons, showed 2.5 cm tumor in the left adrenal gland. On questioning patient had episodic palpitations, flushing and hypertension suggestive of pheochromocytoma. Urinary metanephrine level was of borderline value but serum chromogranin A level was clearly elevated. 123I-MIBG scan showed accumulation of the tracer in the upper left abdomen and the finding was suspected to be intra-adrenal pheochromocytoma. During operation two separate tumors, adrenocortical adenoma in the left adrenal gland, and another smaller, extra-adrenal paraganglioma locating very close to the adenoma, were found. Thus the positive MIBG finding was caused by a paraganglioma with the concurrent presentation of nonfunctioning adrenocortical adenoma.

New amino acid substitutions in the IRS-2 gene in Finnish and Chinese subjects with late-onset type 2 diabetes.

We investigated the significance of the variants of the IRS-2 gene in patients with type 2 diabetes. The entire coding part of the IRS-2 gene was screened by single-strand conformation polymorphism analysis in 40 Chinese and 40 Finnish patients with late-onset type 2 diabetes. The association of the variants of the IRS-2 gene with type 2 diabetes was studied in 85 Finnish diabetic patients and 82 Finnish control subjects and in 100 Chinese diabetic patients and 85 Chinese control subjects. The four variants predicting structural changes in the insulin receptor substrate (IRS)-2 protein included an insertion of AAC (Asn) in the Asn repeat sequence centered around codons 29-36 (allele frequencies of 0 vs. 0.6% and 1.5 vs. 0%), the Ala157Thr substitution (0 vs. 0% and 0.5 vs. 0%), the Leu647Val substitution (0.6 vs. 0% and 0 vs. 0%), and the Gly1057Asp polymorphism (31 vs. 31% and 35 vs. 30%) (P = NS for all comparisons). Furthermore, six silent variants were observed (CGC147CGG, CCC155CCG, GCC156GCT, AGT723AGC, TGT816TGC, and CCC829CCT). The Gly1057Asp polymorphism was not associated with insulin resistance or impaired insulin secretion in Finnish subjects with normal glucose tolerance (n = 295) or impaired glucose tolerance (n = 38). These data indicate that structural variants of the IRS-2 gene were uncommon in Finnish and Chinese patients with type 2 diabetes. Thus, the variants in the coding part of the IRS-2 gene are unlikely to have a major role in the development of type 2 diabetes in Finnish or Chinese subjects.

Long-term association of cardiovascular risk factors with impaired insulin secretion and insulin resistance.

The study aim was to investigate the association of cardiovascular risk factors with insulin resistance and impaired insulin secretion in an 8-year prospective population study in nondiabetic subjects. Cardiovascular risk factors of 271 subjects aged 16 to 61 years were measured at baseline, and insulin sensitivity and acute-phase insulin secretion were assessed by an intravenous glucose tolerance test (IVGTT) and Bergman's minimal model 8 years later. In logistic regression analysis, baseline high-density lipoprotein (HDL) and very-low-density lipoprotein (VLDL) cholesterol (P < .001 and P = .006, respectively), total, low-density lipoprotein (LDL), and VLDL triglycerides (P = .004, P = .048, and P = .002, respectively), apolipoprotein A1 (P = .010), and uric acid (P < .001) were associated with insulin resistance after adjustment for age and the body mass index (BMI). Systolic blood pressure (P = .042) and VLDL cholesterol (P = .018) were associated with impaired insulin secretion after adjustment for age and the BMI. This 8-year longitudinal study demonstrates that dyslipidemia, high blood pressure, and uric acid are associated with insulin resistance, whereas high systolic blood pressure and VLDL cholesterol are associated with impaired first-phase insulin secretion.

Gene encoding the catalytic subunit p110beta of human phosphatidylinositol 3-kinase: cloning, genomic structure, and screening for variants in patients with type 2 diabetes.

Phosphatidylinositol (PI) 3-kinase is a key signaling molecule in insulin-stimulated glucose transport. Therefore, we investigated the catalytic subunit p110beta, of human PI 3-kinase as a candidate gene for type 2 diabetes. Human p110beta gene was cloned from the placental genomic library. All 22 exons, intronic regions flanking the exons and 1.5 kb of the proximal/5' region of the p110beta gene, were screened for variants by single-strand conformation polymorphism analysis in 79 Finnish patients with type 2 diabetes . Allele frequencies of the variants were also determined in 77 nondiabetic control subjects. No variants were found in exons in diabetic patients. However, we identified two nucleotide polymorphisms in the proximal/5' region of the p110beta gene and a variation in the number of 2-bp repeat sequence (TA)n in intron 4. The allele frequencies did not differ between diabetic and control subjects. Our results may indicate that the catalytic subunit p110beta of PI 3-kinase plays such a fundamental role in the insulin-signaling pathway that structural variants are not likely to exist in that gene. The importance of the polymorphisms in the proximal/5' region of the p110beta gene for insulin signaling remains to be determined.

Variants in the hepatocyte nuclear factor-1alpha and -4alpha genes in Finnish and Chinese subjects with late-onset type 2 diabetes.

OBJECTIVE: To determine the role of the hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha genes in the etiology of late-onset type 2 diabetes in Finnish and Chinese subjects. RESEARCH DESIGN AND METHODS: The whole coding regions of the genes encoding for HNF-1alpha and HNF-4alpha, including approximately 800 bp of the HNF-1alpha promoter, were investigated in 40 Finnish subjects (fasting C-peptide 50-570 pmol/l) and 47 Chinese subjects with type 2 diabetes by single-strand conformation polymorphism (SSCP) analysis. Frequencies of the variants of these genes were analyzed by restriction fragment-length polymorphism analysis in additional samples of 100 Finnish diabetic patients and 82 Finnish control subjects and in 58 Chinese diabetic patients and 51 Chinese control subjects. RESULTS: No previously reported gene defects were detected, but one novel functionally silent GCC-->GCG variant (nucleotide 73, exon 10) was observed in the HNF-4alpha gene in a Chinese diabetic patient. Interestingly, the Ala98Val substitution of the HNF-1alpha gene occurred at a significantly higher frequency in 140 Finnish diabetic patients compared with 82 control subjects (P = 0.014). The Ala98Val variant was not, however, associated with abnormalities in insulin secretion evaluated by oral and intravenous glucose tolerance tests in subjects with normal (n = 295) or impaired (n = 38) glucose tolerance. CONCLUSIONS: Variants in the HNF-1alpha and HNF-4alpha genes are unlikely to play a major role in the pathogenesis of late-onset type 2 diabetes in Finnish and Chinese subjects. However, the association of the Ala98Val variant of the HNF-1alpha gene with type 2 diabetes in Finnish subjects may indicate a diabetogenic locus close to the HNF-1alpha gene.

Sulfonylurea receptor 1 gene variants are associated with gestational diabetes and type 2 diabetes but not with altered secretion of insulin.

OBJECTIVE: To investigate the possible association of the variants in the nucleotide binding fold regions of the sulfonylurea receptor 1 (SUR1) gene with gestational diabetes mellitus (GDM), type 2 diabetes, and altered insulin secretion in Finnish subjects. RESEARCH DESIGN AND METHODS: The nucleotide binding fold regions of the SUR1 gene were amplified with polymerase chain reaction and screened by the single-strand conformational polymorphism analysis in 42 subjects with GDM and 40 subjects with type 2 diabetes. Detected variants were further investigated in 377 normoglycemic subjects by restriction fragment-length polymorphism analysis. The effect of the variants of the SUR1 gene on first-phase insulin secretion was studied in 295 normoglycemic subjects. RESULTS: In subjects with GDM or type 2 diabetes, one amino acid change (S1369A), four silent substitutions (R1273R, L829L, T759T, and K649K), and three intron variants were identified in the nucleotide binding fold regions of the SUR1 gene. A tagGCC allele of exon 16 splice acceptor site was more frequent in subjects with GDM (0.55 allele frequency, n = 42) and type 2 diabetes (0.60, n = 40) than in normoglycemic subjects (0.43, n = 377) (P1 = 0.024 and P2 = 0.009, respectively). Similarly, an AGG allele of the R1273R polymorphism was more common in subjects with GDM (0.87) and type 2 diabetes (0.87) than in normoglycemic subjects (0.74) (P1 = 0.009 and P2 = 0.001, respectively). However, the S1369A, R1273R, and cagGCC-->tagGCC variants of the SUR1 gene were not associated with altered first-phase insulin secretion in 295 normoglycemic subjects. CONCLUSIONS: These results suggest that a functional variant that contributes to the risk of GDM and type 2 diabetes may locate close to the SUR1 gene.

Hyperinsulinemia cluster predicts the development of type 2 diabetes independently of family history of diabetes.

OBJECTIVE: The aim of this prospective study was to determine risk factor clusters predicting type 2 diabetes in subjects with and without family history of diabetes by applying factor analyses. RESEARCH DESIGN AND METHODS: The study population consisted of 309 siblings of diabetic (DM+) or nondiabetic (DM-) probands. Risk factors, including lipids, lipoproteins, blood pressure, and glucose tolerance status, were measured at the baseline study and 8 years later. RESULTS: Siblings in the DM+ group had a significantly higher risk of diabetes (odds ratio [OR] = 3.25; P = 0.002) than siblings in the DM- group. Altogether, factor analyses revealed four significant factors in both the DM+ and DM- groups (the percentage of cumulative variance explained 62-66%). Of these, factor 1 (percentage of variance, 27-29%) was characterized by high loadings for BMI, hypertension, glucose area, insulin area (the highest loading), and triglycerides in both the DM+ and DM- groups; therefore, factor 1 can be interpreted as a hyperinsulinemia factor. Also, other factors were essentially similar in both groups. Hyperinsulinemia factor was similarly associated with the risk of developing diabetes in the DM+ group (OR = 4.33, 95% CI 2.29-8.19; P < 0.001) and the DM- group (OR = 4.22, 95% CI 2.02-8.81; P < 0.001) in logistic regression analyses. CONCLUSIONS: Our results indicate that a cluster of cardiovascular risk factors around hyperinsulinemia is an important predictor of diabetes in 8-year follow-up independent of family history of diabetes.

Glucokinase gene islet promoter region variant (G-->A) at nucleotide -30 is not associated with reduced insulin secretion in Finns.

OBJECTIVE: To investigate the effect of the islet promoter region variant (G-->A) at nucleotide -30 of the glucokinase (GCK) gene on insulin levels in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and NIDDM. RESEARCH DESIGN AND METHODS: The study population included 294 subjects with NGT, 83 subjects with IGT, and 36 subjects with NIDDM. Oral glucose tolerance tests (OGTTs) were performed in all subjects, and intravenous glucose tolerance tests (IVGTTs) were performed in subjects with NGT. The islet promoter region of the GCK gene was amplified with polymerase chain reaction and screened for the variant (-30) using single-strand conformation polymorphism analysis. RESULTS: The islet promoter variant (-30) of the GCK gene was found in 17% of subjects with NGT, 23% of subjects with IGT, and 14% of patients with NIDDM (NS between the groups). Fasting, 1-h, and 2-h insulin levels, measured by OGTT, did not differ between subjects with and without this variant in any of the three groups. Furthermore, first-phase insulin secretion, determined by an IVGTT in subjects with NGT, did not associate with presence of the islet promoter region variant (-30) of the GCK gene. CONCLUSIONS: These results indicate that the variant (-30) of the islet promoter region of the GCK gene does not have a significant effect on insulin secretion in Finnish subjects with NGT, IGT, or NIDDM.

New variants in the glycogen synthase gene (Gln71His, Met416Val) in patients with NIDDM from eastern Finland.

Impaired glycogen synthesis after insulin stimulation accounts for most of the insulin resistance in patients with non-insulin-dependent diabetes mellitus (NIDDM). The glycogen synthase gene (GYS1), which encodes the rate-limiting enzyme for glycogen synthesis, is a promising candidate gene for NIDDM. Therefore, we screened all 16 exons of this gene by single-strand conformation polymorphism analysis in 40 patients with NIDDM (age 67 +/- 2 years, body mass index 28.2 +/- 0.6 kg/m2) from Taipalsaari, eastern Finland. The Gly464Ser variant (exon 11) and a silent polymorphism TTC342TTT (exon 7) have been reported previously. In addition, we found a new variant Gln71His (exon 2) and a new amino acid polymorphism Met416Val (exon 10). An additional sample of 65 patients with NIDDM and 82 normoglycaemic men (age 54 +/- 1 years, body mass index 26.3 +/- 1.4 kg/m2) were screened. The allele frequency of the TTC342TTT silent substitution was 0.29 in both NIDDM and normoglycaemic subjects. The Gln71His and Gly464Ser variants were found in 1 (1%) and 3 (3%) subjects, respectively, of the 105 NIDDM patients and in none of the 82 normoglycaemic men. The Met416Val polymorphism was found in 16 (15%) of the 105 NIDDM patients and in 14 (17%) of the 82 control subjects (all heterozygous). The Met416Val polymorphism was not associated with insulin resistance in two groups of normoglycaemic subjects. In conclusion, the new Gln71His and Met416Val substitutions and other variants of the glycogen synthase gene are unlikely to make a major contribution to insulin resistance and NIDDM in diabetic patients from eastern Finland.

The Trp64Arg polymorphism of the beta 3-Adrenergic receptor gene. Lack of association with NIDDM and features of insulin resistance syndrome.

OBJECTIVE: To investigate the association of the Trp64Arg polymorphism of the beta3-adrenergic receptor gene with NIDDM and the features of insulin resistance syndrome in subjects from eastern Finland. RESEARCH DESIGN AND METHODS: We determined the prevalence of the Trp64Arg polymorphism of the beta3-adrenergic receptor gene by restriction fragment length polymorphism analysis in 110 patients with NIDDM (54 men and 56 women, age 63 +/- 1 years, BMI 30.4 +/- 0.5 kg/m2), in 183 patients with features of insulin resistance syndrome (103 men and 80 women, age 44 +/- 0 years, BMI 31.1 +/- 0.4 kb/m2), and in 82 normoglycemic control men (age 54 +/- 1 years, BMI 26.3 +/- 0.4 kg/m2). RESULTS: The allele frequency of the Trp64Arg polymorphism of the beta3-adrenergic receptor gene was similar in patients with NIDDM, in patients with insulin resistance syndrome, and in control subjects (0.08, 0.07, and 0.07, respectively; NS). In addition, this polymorphism was not associated with low resting metabolic rate, abdominal obesity, increased lipid oxidation, hypertension, or earlier development of NIDDM as previously described. Furthermore, in 82 normoglycemic male control subjects the Trp64Arg polymorphism was not associated with insulin resistance evaluated by the euglycemic-hyperinsulinemic clamp. CONCLUSIONS: The Trp64Arg polymorphism of the beta 3-adrenergic receptor gene is unlikely to be a major genetic predisposer to NIDDM or insulin resistance syndrome in subjects from eastern Finland.

Femoral atherosclerosis in middle-aged subjects: association with cardiovascular risk factors and insulin resistance.

The aim of this 8-year follow-up study was to investigate the role of conventional cardiovascular risk factors as predictors for asymptomatic femoral atherosclerosis. The authors also evaluated the association of insulin resistance with atherosclerosis in a cross-sectional setting. Cardiovascular risk factors of 118 subjects were studied at the baseline study in 1983-1985 in Kuopio, Finland. Femoral atherosclerosis, defined as a presence of plaques, was investigated by ultrasonography in the follow-up study in 1992-1993. In the univariate logistic regression analyses, age (p = 0.002), systolic and diastolic blood pressure (p = 0.002 and p = 0.013, respectively), total cholesterol (p = 0.005), low density lipoprotein (LDL) cholesterol (p = 0.005), total triglycerides (p = 0.033), LDL triglycerides (p = 0.033), apolipoprotein B (p = 0.045), and fasting plasma glucose (p = 0.011) had a significant association with the presence of femoral plaques. Plasma insulin levels and insulin sensitivity index, determined in 87 subjects by an intravenous glucose tolerance test and minimal model at the follow-up study, were not associated with femoral plaques. The results demonstrate that atherogenic lipid and lipoprotein pattern and blood pressure are strongly associated with femoral atherosclerosis, whereas insulin sensitivity and hyperinsulinemia seem not to play such a significant role.

Family history of coronary heart disease is a stronger predictor of coronary heart disease morbidity and mortality than family history of non-insulin dependent diabetes mellitus.

The aim of this study was to compare the effect of family history of non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD) as risk factors for CHD morbidity and mortality. Altogether, 394 siblings of NIDDM probands and non-diabetic probands, with and without CHD, were followed for 8 years with respect to CHD events in a prospective population-based study. The baseline study was conducted from 1983 to 1985. Age- and sex-adjusted cumulative occurrence of CHD events was higher in the siblings of the probands with CHD and with NIDDM (13.1%; P = 0.037) and in the siblings of the probands with CHD and without NIDDM (15.4%; P = 0.054), compared with the siblings of the probands without NIDDM and without CHD (4.8%). The incidence of fatal CHD events tended to be higher in a group with a family history of NIDDM and CHD, but the trend was not statistically significant. In univariate logistic regression analyses, a family history of CHD was positively associated with cumulative occurrence of CHD events (odds ratio 2.53, P = 0.009), whereas a family history of NIDDM had no significant association (odds ratio 1.39, P = 0.312). After adjustment for age, sex, family history of NIDDM and major cardiovascular risk factors, the association between family history of CHD and cumulative occurrence of CHD events remained significant (odds ratio 2.25, P = 0.048). In conclusion, the present study indicates that a family history of CHD is a stronger predictor of future CHD events than a family history of NIDDM.

Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance.

Skeletal muscle and adipose tissue hexokinase II is a promising candidate gene for non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance. Therefore, we investigated the association of alleles at four polymorphic loci in this gene with NIDDM and insulin resistance in 110 Finnish diabetic patients with NIDDM and in 97 Finnish control subjects with normal glucose tolerance and a negative family history of diabetes. The four polymorphic nucleotide substitutions (silent) in the coding region of the hexokinase II gene were: GAC 251 GAT (exon 7), AAC 692 AAT and CCG 736 CCC (exon 15), and CTG 766 CTA (exon 16). Allele frequencies of each of these polymorphisms did not differ between patients with NIDDM and control subjects. In addition, subjects who were homozygous for the less frequent allele of each of the four polymorphisms had a similar degree of insulin resistance, as determined by the euglycaemic clamp technique, as did the subjects who were homozygous for the common allele in both control subjects and in patients with NIDDM. In conclusion, polymorphisms in the hexokinase II gene are not associated with the risk of NIDDM or insulin resistance in the Finnish population.

Glucokinase gene variants in subjects with late-onset NIDDM and impaired glucose tolerance.

OBJECTIVE: To investigate the frequency of variants of the glucokinase (GCK) gene in subjects with late-onset non-insulin-dependent diabetes mellitus (NIDDM) and in subjects with late-onset impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: The study population included 36 Finnish patients with late-onset NIDDM who were treated with diet for > 8 years or who were newly diagnosed and 40 subjects with late-onset IGT who had low or normal insulin levels when tested by an oral glucose tolerance test. All exons, exon-intron junctions, and islet and liver promotor regions of the GCK gene were amplified with the polymerase chain reaction and screened for mutations using single-strand conformation polymorphism analysis. RESULTS: A silent third-base substitution (TAC: >TAT) in codon 215 of exon 6 was found in 2.8% of NIDDM patients and in 5.0% of IGT subjects. Polymorphisms were found in islet exon 1 at nucleotide 403 (C-->G) in 16.7% of NIDDM patients and in 17.5% of IGT subjects and in the noncoding region of the islet promotor at nucleotide -30 (G-->A) in 13.9% of NIDDM patients and in 25.0% of IGT subjects. Furthermore, in liver intron 1 a variant (C-->T), 12 base pairs upstream from the splice acceptor site, was found in 5.6% of NIDDM patients and in 7.5% of IGT subjects. CONCLUSIONS: These results indicate that the mutations in the coding region of the GCK gene are not likely to play a major role the pathogenesis of late-onset NIDDM or IGT in the Finnish population.

Insulin receptor substrate-1 variants in non-insulin-dependent diabetes.

Insulin receptor substrate-1 (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. Therefore, we investigated the frequency and clinical significance of variants in the coding region of this gene in patients with non-insulin-dependent diabetes (NIDDM). Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM. Applying single strand conformation polymorphism analysis the following amino acid substitutions were found among the 40 NIDDM patients: Gly818-Arg, Ser892Gly, and Gly971Arg. The first two variants have not been previously reported. Additional samples of 72 patients with NIDDM and 104 healthy control subjects with completely normal oral glucose tolerance test and a negative family history of diabetes were screened. The most common polymorphism was the Gly971Arg substitution which was found in 11 (9.8%) of 112 NIDDM patients and in 9 (8.7%) of 104 control subjects. The Gly818Arg substitution was found in 2 (1.8%) of NIDDM patients and in 2 (1.9%) of control subjects, and the Ser892Gly substitution was found in 3 (2.7%) NIDDM patients and in 1 (1.0%) control subject. The Gly971Arg substitution was not associated with an impairment in insulin secretion capacity (estimated by insulin responses in an oral glucose tolerance test or by the hyperglycemic clamp) or insulin action (estimated by the euglycemic clamp). Of the three amino acid substitutions observed Ser892Gly is the most interesting one since it abolishes one of the potential serine phosphorylation sites (SPGE) which is located immediately NH2-terminal to the only SH2 binding site of growth factor receptor-bound protein (GRB2), and thus could potentially influence some aspects of signal transduction and metabolic response to insulin.